Proposing BCG Vaccination for Mycobacterium avium ss. paratuberculosis (MAP) Associated Autoimmune Diseases

Coad Thomas Dow, Coad Thomas Dow

Abstract

Bacille Calmette-Guerin (BCG) vaccination is widely practiced around the world to protect against the mycobacterial infection tuberculosis. BCG is also effective against the pathogenic mycobacteria that cause leprosy and Buruli's ulcer. BCG is part of the standard of care for bladder cancer where, when given as an intravesicular irrigant, BCG acts as an immunomodulating agent and lessens the risk of recurrence. Mycobacterium avium ss. paratuberculosis (MAP) causes a fatal enteritis of ruminant animals and is the putative cause of Crohn's disease of humans. MAP has been associated with an increasingly long list of inflammatory/autoimmune diseases: Crohn's, sarcoidosis, Blau syndrome, Hashimoto's thyroiditis, autoimmune diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis, lupus and Parkinson's disease. Epidemiologic evidence points to BCG providing a "heterologous" protective effect on assorted autoimmune diseases; studies using BCG vaccination for T1D and MS have shown benefit in these diseases. This article proposes that the positive response to BCG in T1D and MS is due to a mitigating action of BCG upon MAP. Other autoimmune diseases, having a concomitant genetic risk for mycobacterial infection as well as cross-reacting antibodies against mycobacterial heat shock protein 65 (HSP65), could reasonably be considered to respond to BCG vaccination. The rare autoimmune disease, relapsing polychondritis, is one such disease and is offered as an example. Recent studies suggesting a protective role for BCG in Alzheimer's disease are also explored. BCG-induced energy shift from oxidative phosphorylation to aerobic glycolysis provides the immunomodulating boost to the immune response and also mitigates mycobacterial infection-this cellular mechanism unifies the impact of BCG on the disparate diseases of this article.

Keywords: Alzheimer’s; BCG; Bacille Calmette–Guerin; Buruli’s ulcer; HSP65; Johne’s; MAP; Mycobacterium avium ss. paratuberculosis; NTM; Old Friends; Warburg effect; aerobic glycolysis; autoimmune; bladder cancer; diabetes; heat shock protein; immunosenescence; leprosy; molecular mimicry; multiple sclerosis; non-specific effects; non-tuberculosis mycobacteria; relapsing polychondritis; tuberculosis; vaccine; zoonosis.

Conflict of interest statement

The author declare no conflict of interest.

References

    1. McShane H. Tuberculosis Vaccines: Beyond Bacille Calmette-Guerin. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2011;366:2782–2789. doi: 10.1098/rstb.2011.0097.
    1. Ottenhoff T.H.M., Kaufmann S.H.E. Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go? PLoS Pathog. 2012;8:e1002607-12. doi: 10.1371/journal.ppat.1002607.
    1. Zimmermann P., Finn A., Curtis N. Does BCG Vaccination Protect Against Nontuberculous Mycobacterial Infection? A Systematic Review and Meta-Analysis. J. Infect. Dis. 2018;218:679–687. doi: 10.1093/infdis/jiy207.
    1. Zheng Y.Q., Naguib Y.W., Dong Y., Shi Y.C., Bou S., Cui Z. Applications of bacillus Calmette-Guerin and recombinant bacillus Calmette-Guerin in vaccine development and tumor immunotherapy. Expert Rev. Vaccines. 2015;14:1255–1275. doi: 10.1586/14760584.2015.1068124.
    1. Dow C.T., Sechi L.A. Cows Get Crohn’s Disease and They’re Giving Us Diabetes. Microorganisms. 2019;7:466. doi: 10.3390/microorganisms7100466.
    1. Ristori G., Faustman D., Matarese G., Romano S., Salvetti M. Bridging the gap between vaccination with Bacille Calmette-Guérin (BCG) and immunological tolerance: The cases of type 1 diabetes and multiple sclerosis. Curr. Opin. Immunol. 2018;55:89–96. doi: 10.1016/j.coi.2018.09.016.
    1. Calmette A. Preventive vaccination against tuberculosis with BCG. Proc. R. Soc. Med. 1931;24:1481–1490. doi: 10.1177/003591573102401109.
    1. Ottenhoff T.H.M. Overcoming the Global Crisis: “yes, we can,” but also for TB? Eur. J. Immunol. 2009;39:2014–2020. doi: 10.1002/eji.200939518.
    1. Kaufmann S.H.E., Winau F. From Bacteriology to Immunology: The Dualism of Specificity. Nat. Immunol. 2005;6:s1063–s1066. doi: 10.1038/ni1105-1063.
    1. Kaufmann S.H., Hussey G., Lambert P.H. New vaccines for tuberculosis. Lancet. 2010;375:2110–2119. doi: 10.1016/S0140-6736(10)60393-5.
    1. Luca S., Mihaescu T. History of BCG Vaccine. Maedica. 2013;8:53–58.
    1. Milstien J.B., Gibson J.J. Quality Control of BCG Vaccine by WHO: A Review of Factors that May Influence Vaccine Effectiveness and Safety. Bull. World Health Organ. 1990;68:93–108.
    1. Palmer C.E., Long M.W. Effects of Infection with Atypical Mycobacteria on BCG Vaccination and Tuberculosis. Am. Rev. Respir. Dis. 1966;94:553–568.
    1. Griffin J.F., Chinn D.N., Rodgers C.R., Mackintosh C.G. Optimal models to evaluate the protective efficacy of tuberculosis vaccines. Tuberculosis. 2001;81:133–139. doi: 10.1054/tube.2000.0271.
    1. Gengenbacher M., Nieuwenhuizen N.E., Kaufmann S. BCG—Old workhorse, new skills. Curr. Opin. Immunol. 2017;47:8–16. doi: 10.1016/j.coi.2017.06.007.
    1. World Health Organization BCG vaccines: WHO position paper—February 2018. Wkly. Epidemiol. Rec. 2018;93:73–96.
    1. Donohue M.J. Increasing nontuberculous mycobacteria reporting rates and species diversity identified in clinical laboratory reports. BMC Infect. Dis. 2018;18:163. doi: 10.1186/s12879-018-3043-7.
    1. Henkle E., Hedberg K., Schafer S., Novosad S., Winthrop L. Population-based incidence of pulmonary nontuberculous mycobacterial disease in Oregon 2007 to 2012. Ann. Am. Thorac. Soc. 2015;12:642–647. doi: 10.1513/AnnalsATS.201412-559OC.
    1. Namkoong H., Kurashima A., Morimoto K., Hoshino Y., Hasegawa N., Ato M., Mitarai S. Epidemiology of pulmonary nontuberculous mycobacterial disease in Japan. Emerg. Infect. Dis. 2016;22:1116–1117. doi: 10.3201/eid2206.151086.
    1. Shah N.M., Davidson J.A., Anderson L.F., Lator M.K., Kim J., Thomas H.L., Lipman M., Abubakar I. Pulmonary Mycobacterium avium-intracellulare is the main driver of the rise in non-tuberculous mycobacteria incidence in England, Wales and Northern Ireland, 2007–2012. BMC Infect. Dis. 2016;16:195. doi: 10.1186/s12879-016-1521-3.
    1. Lacroix A., Piau C., Lanotte P., Carricajo A., Guillouzouic A., Peuchant O., Cady A., Dupin C., Fangous M.-S., Martin C., et al. Emergence of nontuberculous mycobacterial lymphadenitis in children after the discontinuation of mandatory Bacillus Calmette and Guérin immunization in France. Pediatr. Infect. Dis. J. 2018;37:e257–e260. doi: 10.1097/INF.0000000000001977.
    1. Romanus V., Hallander H.O., Wahlen P., Olinder-Nielsen A.M., Magnusson P.H., Juhlin I. Atypical mycobacteria in extrapulmonary disease among children. Incidence in Sweden from 1969 to 1990, related to changing BCG-vaccination coverage. Tuber. Lung Dis. 1995;76:300–310. doi: 10.1016/S0962-8479(05)80028-0.
    1. Trnka L., Danková D., Svandová E. Six years’ experience with the discontinuation of BCG vaccination. 4. Protective effect of BCG vaccination against the Mycobacterium avium intracellulare complex. Tuber. Lung Dis. 1994;75:348–352. doi: 10.1016/0962-8479(94)90080-9.
    1. Katila M.L., Brander E., Backman A. Neonatal BCG vaccination and mycobacterial cervical adenitis in childhood. Tubercle. 1987;68:291–296. doi: 10.1016/0041-3879(87)90070-5.
    1. World Health Organization Report on BCG Vaccine Use for Protection against Mycobacterial Infections Including Tuberculosis, Leprosy, and Other Nontuberculous Mycobacteria (NTM) Infection. [(accessed on 1 October 2017)]; Available online: .
    1. WHO Health Topics. Leprosy. [(accessed on 19 October 2019)]; Available online: .
    1. Setia M.S., Steinmaus C., Ho C.S., Rutherford G.W. The role of BCG in prevention of leprosy: A meta-analysis. Lancet Infect. Dis. 2006;6:162–170. doi: 10.1016/S1473-3099(06)70412-1.
    1. Karonga Prevention Trial Group Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet. 1996;348:17–24. doi: 10.1016/S0140-6736(96)02166-6.
    1. Merle C.S., Cunha S.S., Rodrigues L.C. BCG vaccination and leprosy protection: Review of current evidence and status of BCG in leprosy control. Expert Rev. Vaccines. 2010;9:209–222. doi: 10.1586/erv.09.161.
    1. Yotsu R.R., Suzuki K., Simmonds R.E., Bedimo R., Ablordey A., Yeboah-Manu D., Pillips R., Asiedu K. Buruli Ulcer: A Review of the Current Knowledge. Curr. Trop. Med. Rep. 2018;5:247–256. doi: 10.1007/s40475-018-0166-2.
    1. MacCallum P., Tolhurst J.C., Buckle G., Sissons H.A. A new mycobacterial infection in man. J. Pathol. Bacteriol. 1948;60:93–122. doi: 10.1002/path.1700600111.
    1. Janssens P.G., Quertinmont M.J., Sieniawski J., Gatti F. Necrotic tropical ulcers and mycobacterial causative agents. Trop. Geogr. Med. 1959;11:293–312.
    1. Clancey J.K., Dodge O.G., Lunn H.F., Oduori M.L. Mycobacterial skin ulcers in Uganda. Lancet. 1961;2:951–954. doi: 10.1016/S0140-6736(61)90793-0.
    1. Asiedu K., Hayman J. Epidemiology. In: Asiedu K., Scherpbier R., Raviglione M., editors. Buruli Ulcer: Mycobacterium Ulcerans Infection. World Health Organization; Geneva, Switzerland: 2000.
    1. World Health Organization . WHO Joins Battle Against a New Emerging Disease, Buruli Ulcer. World Health Organization; Geneva, Switzerland: 1997.
    1. World Health Organization Buruli ulcer disease: Mycobacterium ulcerans infection: Background = Ulcère de Buruli: Infection à Mycobacterium ulcerans: Généralités. Wkly. Epidemiol. Rec. Relevé Épidémiologique Hebdomadaire. 2003;78:163–168.
    1. Portaels F., Aguiar J., Debacker M., Guédénon A., Steunou C., Zinsou C., Meyers W.M. Mycobacterium bovis BCG vaccination as prophylaxis against Mycobacterium ulcerans osteomyelitis in Buruli ulcer disease. Infect. Immun. 2004;72:62–65. doi: 10.1128/IAI.72.1.62-65.2004.
    1. Smith P.G., Revill W.D., Lukwago E., Rykushin Y.P. The protective effect of BCG against Mycobacterium ulcerans disease: A controlled trial in an endemic area of Uganda. Trans. R. Soc. Trop. Med. Hyg. 1976;70:449–457. doi: 10.1016/0035-9203(76)90128-0.
    1. Uganda Buruli Group BCG vaccination against Mycobacterium ulcerans infection (Buruli ulcer). First results of a trial in Uganda. Lancet. 1969;1:111–115.
    1. Davis W.C., Park K.T. Progress Towards Control of a Mycobacterial Pathogen, Mycobacterium avium subsp. paratuberculosis, the Causative Agent of Johne’s Disease in Cattle and Humans. J. Food Hyg. Saf. 2018;33:221–228. doi: 10.13103/JFHS.2018.33.4.221.
    1. Balseiro A., Perez V., Juste R.A. Chronic regional intestinal inflammatory disease: A trans-species slow infection? Comp. Immunol. Microbiol. Infect. Dis. 2019;62:88–100. doi: 10.1016/j.cimid.2018.12.001.
    1. Davis W.C., Kuenstner J.T., Singh S.V. Resolution of Crohn’s (Johne’s) disease with antibiotics: What are the next steps? Expert Rev. Gastroenterol. Hepatol. 2017;21:1–4. doi: 10.1080/17474124.2017.1300529.
    1. Chaubey K.K., Singh S.V., Gupta S., Singh M., Sohal J.S., Kumar N., Singh M.K., Bhatia A.K., Dhama K. Mycobacterium avium subspecies paratuberculosis—An important food borne pathogen of high public health significance with special reference to India. An Update. Vet. Q. 2017;37:282–299. doi: 10.1080/01652176.2017.1397301.
    1. Feller M., Huwiler K., Stephan R., Altpeter E., Shang A., Furrer H., Pfyer G.E., Jemmi T., Baumgartner A., Egger M. Mycobacterium avium subspecies paratuberculosis and Crohn’s disease: A systematic review and meta-analysis. Lancet Infect. Dis. 2007;7:607–613. doi: 10.1016/S1473-3099(07)70211-6.
    1. Abubakar I., Myhill D., Aliyu S.H., Hunter P.R. Detection of Mycobacterium avium subspecies paratuberculosis from patients with Crohn’s disease using nucleic acid-based techniques: A systematic review and meta-analysis. Inflamm. Bowel. Dis. 2008;14:401–410. doi: 10.1002/ibd.20276.
    1. Sechi L.A., Dow C.T. Mycobacterium avium ss. paratuberculosis Zoonosis—The Hundred Year War–Beyond Crohn’s Disease. Front. Immunol. 2015;6:96. doi: 10.3389/fimmu.2015.00096.
    1. Dow C.T., Ellingson J.L.E. Detection of Mycobacterium avium ss. paratuberculosis in Blau Syndrome Tissues. Autoimmune Dis. 2010;2010:1–5. doi: 10.4061/2010/127692.
    1. Sechi L.A., Gazouli M., Ikonomopoulos J., Lukas J.C., Scanu A.M., Ahmed N., Fadda G., Zanetti S. Mycobacterium avium subsp. paratuberculosis, genetic susceptibility to Crohn’s disease, and Sardinians: The way ahead. J. Clin. Microbiol. 2005;43:5275–5277. doi: 10.1128/JCM.43.10.5275-5277.2005.
    1. Dow C.T.M. paratuberculosis Heat Shock Protein 65 and Human Diseases: Bridging Infection and Autoimmunity. Autoimmune Dis. 2012;2012:1–6. doi: 10.1155/2012/150824.
    1. Wang H., Yuan F.F., Dai Z.W., Wang B., Ye D.Q. Association between rheumatoid arthritis and genetic variants of natural resistance-associated macrophage protein 1 gene: A meta-analysis. Int. J. Rheum Dis. 2018;21:1651–1658. doi: 10.1111/1756-185X.13366.
    1. Sechi L.A., Gazouli M., Sieswerda L.E., Molicotti P., Ahmed N., Ikonomopoulos J., Scanu A.M., Paccagnini D., Zanetti S. Relationship between Crohn’s disease, infection with Mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in Sardinian patients. World J. Gastroenterol. 2006;12:7161–7164. doi: 10.3748/wjg.v12.i44.7161.
    1. Dow C.T.M. paratuberculosis and Parkinson’s disease—Is this a trigger. Med. Hypotheses. 2014;83:709–712. doi: 10.1016/j.mehy.2014.09.025.
    1. Härtlova A., Herbst S., Peltier J., Rodgers A., Bilkei-Gorzo O., Fearns A., Dill B.D., Lee H., Flynn R., Cowley S.A., et al. LRRK2 is a negative regulator of Mycobacterium tuberculosis phagosome maturation in macrophages. EMBO J. 2018;37:e98694. doi: 10.15252/embj.201798694.
    1. Sharp R.C., Beg S.A., Naser S.A. Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Linked to Hyper-Proliferative T-Cells and Susceptibility to Mycobacteria in Rheumatoid Arthritis. Front. Microbiol. 2018;8:11. doi: 10.3389/fcimb.2018.00011.
    1. Dow C.T. Paratuberculosis and Type I diabetes: Is this the trigger? Med. Hypotheses. 2006;67:782–785. doi: 10.1016/j.mehy.2006.04.029.
    1. Cossu D., Masala S., Cocco E., Paccagnini D., Tranquilli S., Frau J., Marrosu M.G., Sechi L.A. Association of Mycobacterium avium subsp. paratuberculosis and SLC11A1 polymorphisms in Sardinian multiple sclerosis patients. J. Infect. Dev. Ctries. 2013;7:203–207. doi: 10.3855/jidc.2737.
    1. Gong L., Liu B., Wang J., Pan H., Qi A., Zhang S., Wu J., Yang P., Wang B. Novel missense mutation in PTPN22 in a Chinese pedigree with Hashimoto’s thyroiditis. BMC Endocr. Disord. 2018;18:76. doi: 10.1186/s12902-018-0305-8.
    1. D’Amore M., Lisi S., Sisto M., Cucci L., Dow C.T. Molecular identification of Mycobacterium avium subspecies paratuberculosis in an Italian patient with Hashimoto’s thyroiditis and Melkersson-Rosenthal syndrome. J. Med. Microbiol. 2010;59:137–139. doi: 10.1099/jmm.0.013474-0.
    1. Sisto M., Cucci L., D’Amore M., Dow T.C., Mitolo V., Lisi S. Proposing a relationship between Mycobacterium avium subspecies paratuberculosis infection and Hashimoto’s thyroiditis. Scand. J. Infect. Dis. 2010;42:787–790. doi: 10.3109/00365541003762306.
    1. Arru G., Caggiu E., Paulus K., Sechi G.P., Mameli G., Sechi L.A. Is there a role for Mycobacterium avium subspecies paratuberculosis in Parkinson’s disease? J. Neuroimmunol. 2016;293:86–90. doi: 10.1016/j.jneuroim.2016.02.016.
    1. Bo M., Erre G.L., Niegowska M., Piras M., Taras L., Longu M.G., Passiu G., Sechi L.A. Interferon regulatory factor 5 is a potential target of autoimmune response triggered by Epstein-barr virus and Mycobacterium avium subsp. paratuberculosis in rheumatoid arthritis, investigating a mechanism of molecular mimicry. Clin. Exp. Rheumatol. 2018;36:376–381.
    1. Dow C.T. Detection of M. paratuberculosis Bacteremia in a Child with Lupus Erythematosus and Sjogren’s Syndrome. Autoimmun. Infect. Dis. 2016;2:127692.
    1. Paccagnini D., Sieswerda L., Rosu V., Masala S., Pacifico A., Gazouli M., Ikonomopoulos J., Ahmed N., Zanetti S., Sechi L.A. Linking Chronic Infection and Autoimmune Diseases: Mycobacterium avium Subspecies paratuberculosis, SLC11A1 Polymorphisms and Type-1 Diabetes Mellitus. PLoS ONE. 2009;4:e7109. doi: 10.1371/journal.pone.0007109.
    1. Kuenstner J.T., Naser S., Chamberlin W., Borody T., Graham D.Y., McNees A., Hermon-Taylor J., Hermon-Taylor A., Dow C.T., Thayer W., et al. The Consensus from the Mycobacterium avium ssp. paratuberculosis (MAP) Conference 2017. Front. Public Health. 2017;5:208. doi: 10.3389/fpubh.2017.00208.
    1. Lombard J.E., Gardner I.A., Jafarzadeh S.R., Fossler C.P., Harris B., Capsel B.R. Herd-level prevalence of Mycobacterium avium subsp. paratuberculosis infection in United States dairy herds in 2007. Prev. Vet. Med. 2013;108:234–238. doi: 10.1016/j.prevetmed.2012.08.006.
    1. Millar D., Ford J., Sanderson J., Withey S., Tizard M., Doran T., Hermon-Taylor J. IS900 PCR to detect Mycobacterium paratuberculosis in retail supplies of whole pasteurized cows’ milk in England and Wales. Appl. Environ. Microbiol. 1996;62:3446–3452. doi: 10.1128/AEM.62.9.3446-3452.1996.
    1. Ellingson J.L., Anderson J.L., Koziczkowski J.J., Radcli R.P., Sloan S.J., Allen S.E. Detection of viable Mycobacterium avium subsp. paratuberculosis in retail pasteurized whole milk by two culture methods and PCR. J. Food Prot. 2005;68:966–972. doi: 10.4315/0362-028X-68.5.966.
    1. Hruska K., Bartos M., Kralik P., Pavlik I. Mycobacterium avium subsp. paratuberculosis in powdered infant milk: Paratuberculosis in cattle—The public health problem to be solved. Vet. Med. Czech. 2005;50:327–335. doi: 10.17221/5631-VETMED.
    1. Pickup R.W., Rhodes G., Arnott S., Sidi-Boumedine K., Bull T.J., Weightman A. Mycobacterium avium subsp. paratuberculosis in the catchment area and water of the River Taff in South Wales, United Kingdom, and its potential relationship to clustering of Crohn’s disease cases in the city of Cardiff. Appl. Environ. Microbiol. 2003;71:2130–2139. doi: 10.1128/AEM.71.4.2130-2139.2005.
    1. Whan L., Ball H.J., Grant I.R., Rowe M.T. Occurrence of Mycobacterium avium subsp. Paratuberculosis in untreated water in Northern Ireland. Appl. Environ. Microbiol. 2006;71:7107–7112. doi: 10.1128/AEM.71.11.7107-7112.2005.
    1. Pickup R.W., Rhodes G., Bull T.J., Arnott S., Sidi-Boumedine K., Hurley M., Hermon-Taylor J. Mycobacterium avium subsp. paratuberculosis in Lake Catchments, in River Water Abstracted for Domestic Use, and in Effluent from Domestic Sewage Treatment Works: Diverse Opportunities for Environmental Cycling and Human Exposure. Appl. Environ. Microbiol. 2006;72:4067–4077. doi: 10.1128/AEM.02490-05.
    1. Richardson H., Rhodes G., Henrys P., Sedda L., Weightman A.J., Pickup R.W. Presence of Mycobacterium avium Subspecies paratuberculosis Monitored Over Varying Temporal and Spatial Scales in River Catchments: Persistent Routes for Human Exposure. Microorganisms. 2019;7:136. doi: 10.3390/microorganisms7050136.
    1. Heinzmann J., Wilkens M., Dohmann K., Gerlach G.F. Mycobacterium avium subsp. paratuberculosis-specific mpt operon expressed in M. bovis BCG as vaccine candidate. Vet. Microbiol. 2008;130:330–337. doi: 10.1016/j.vetmic.2008.01.014.
    1. Stratmann J., Strommenger B., Goethe R., Dohmann K., Gerlach G.-F., Stevenson K., Li L.L., Zhang Q., Kapur V., Bull T.J. A 38-kilobase pathogenicity island specific for Mycobacterium avium subsp paratuberculosis encodes cell surface proteins expressed in the host. Infect. Immun. 2004;72:1265–1274. doi: 10.1128/IAI.72.3.1265-1274.2004.
    1. Goodridge H., Ahmed S., Curtis N., Kollmann T., Levy O., Netea M., Pollard A., vanCrevel R., Wilson C. Harnessing the beneficial heterologous effects of vaccination. Nat. Rev. Immunol. 2016;16:392–400. doi: 10.1038/nri.2016.43.
    1. Faustman D.L., Wang L., Okubo Y., Burger D., Ban L., Man G., Zheng H., Schoenfeld D., Pompei R., Avruch J., et al. Proof-of-concept, randomized, controlled clinical trial of Bacillus–Calmette–Guerin for treatment of long-term type 1 diabetes. PLoS ONE. 2012;7:e41756. doi: 10.1371/journal.pone.0041756.
    1. Faustman D.L., editor. The Value of BCG and TNF in Autoimmunity. 1st ed. Academic Press; Amsterdam, The Netherlands: 2014. TNF, BCG, and the Proteasome in Auto-Immunity: An Overview of the Pathways & Results of a Phase I Study in Type 1 Diabetes; pp. 81–104.
    1. Ristori G., Romano S., Cannoni S., Visconti A., Tinelli E., Mendozzi L., Cecconi P., Lanzillo R., Quarantelli M., Buttinelli C., et al. Effects of bacille Calmette–Guerin after the first demyelinating event in the CNS. Neurology. 2014;82:41–48. doi: 10.1212/01.wnl.0000438216.93319.ab.
    1. Arnoldussen D.L., Linehan M., Sheikh A. BCG vaccination and allergy: A systematic review and meta-analysis. J. Allergy Clin. Immunol. 2011;127:246–253.e21. doi: 10.1016/j.jaci.2010.07.039.
    1. Shann F. The nonspecific effects of vaccines and the expanded program on immunization. J. Infect. Dis. 2011;204:182–184. doi: 10.1093/infdis/jir244.
    1. Kristensen I., Aaby P., Jensen H. Routine vaccinations and child survival: Follow up study in Guinea-Bissau, West Africa. BMJ. 2000;321:1435–1438. doi: 10.1136/bmj.321.7274.1435.
    1. Karaci M. The Protective Effect of the BCG Vaccine on the Development of Type 1 Diabetes in Humans. In: Faustman D., editor. The Value of BCG and TNF in Autoimmunity. 1st ed. Academic Press; Amsterdam, The Netherlands: 2014. pp. 52–62.
    1. Masala S., Zedda M.A., Cossu D., Ripoli C., Palermo M., Sechi L.A. Zinc Transporter 8 and MAP3865c Homologous Epitopes are Recognized at T1D Onset in Sardinian Children. PLoS ONE. 2013;8:e63371. doi: 10.1371/journal.pone.0063371.
    1. Kiraly N., Allen K.J., Curtis N. BCG for the prevention of food allergy—Exploring a new use for an old vaccine. Med. J. Aust. 2015;202:565–566. doi: 10.5694/mja14.01511.
    1. Kuusisto H., Kaprio J., Kinnunen E., Luukkaala T., Koskenvuo M., Elovaara I. Concordance and heritability of multiple sclerosis in Finland: Study on a nationwide series of twins. Eur. J. Neurol. 2008;15:1106–1110. doi: 10.1111/j.1468-1331.2008.02262.x.
    1. Knip M. Pathogenesis of type 1 diabetes: Implications for incidence trends. Horm. Res. Paediatr. 2011;76:57–64. doi: 10.1159/000329169.
    1. Kleinnijenhuis J., Quintin J., Preijers F., Joosten L.A., Ifrim D.C., Saeed S., Jacobs C., van Loenhout J., de Jong D., Stunnenberg H.G., et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl. Acad. Sci. USA. 2012;109:17537–17542. doi: 10.1073/pnas.1202870109.
    1. Aaby P., Benn C.S. Stopping live vaccines after disease eradication may increase mortality. Vaccine. 2020;38:10–14. doi: 10.1016/j.vaccine.2019.10.034.
    1. Aaby P., Benn C.S. Saving lives by training innate immunity with bacille Calmette-Guerin vaccine. Proc. Natl. Acad. Sci. USA. 2012;109:17317–17318. doi: 10.1073/pnas.1215761109.
    1. Pearl R. Cancer and tuberculosis. Am. J. Hyg. 1929;9:97–159. doi: 10.1093/oxfordjournals.aje.a121646.
    1. Holmgren I. Employment of B. C. G. especially in Intravenous Injection. Acta Med. Scand. 1936;90:350–361. doi: 10.1111/j.0954-6820.1936.tb15958.x.
    1. Morton D., Eilber F.R., Malmgren R.A., Wood W.C. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery. 1970;68:158–163.
    1. Rosenberg S.A., Rapp H.J. Intralesional immunotherapy of melanoma with BCG. Med. Clin. N. Am. 1976;60:419–430. doi: 10.1016/S0025-7125(16)31889-2.
    1. Askeland E.J., Newton M.R., O’Donnell M.A., Luo Y. Bladder Cancer Immunotherapy: BCG and Beyond. Adv. Urol. 2012;2012:181987. doi: 10.1155/2012/181987.
    1. Gontero P., Bohle A., Malmstrom P.U., O’Donnell M.A., Oderda M., Sylvester R., Witjes F. The role of bacillus Calmette-Guerin in the treatment of non-muscle-invasive bladder cancer. Eur. Urol. 2010;57:410–429. doi: 10.1016/j.eururo.2009.11.023.
    1. Morales A., Eidinger D., Bruce A.W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 1976;116:180–183. doi: 10.1016/S0022-5347(17)58737-6.
    1. Babjuk M., Oosterlinck W., Sylvester R., Kaasinen E., Bohle A., Palou-Redorta J., Roupret M. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur. Urol. 2011;59:997–1008. doi: 10.1016/j.eururo.2011.03.017.
    1. Chou R., Selph S., Buckley D.I., Fu R., Griffin J.C., Grusing S., Gore J.L. Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis. J. Urol. 2017;197:1189–1199. doi: 10.1016/j.juro.2016.12.090.
    1. Brandau S., Suttmann H. Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: A success story with room for improvement. Biomed. Pharmacother. 2007;61:299–305. doi: 10.1016/j.biopha.2007.05.004.
    1. Pettenati C., Ingersoll M.A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 2018;15:615–625. doi: 10.1038/s41585-018-0055-4.
    1. Taniguchi K., Koga S., Nishikido M., Yamashita S., Sakuragi T., Kanetake H., Saito Y. Systemic immune response after intravesical instillation of Bacille Calmette-Guerin (BCG) for superficial bladder cancer. Clin. Exp. Immunol. 1999;115:131–135. doi: 10.1046/j.1365-2249.1999.00756.x.
    1. Atkinson M.A. The Pathogenesis and Natural History of Type 1 Diabetes. Cold Spring Harb. Perspect. Med. 2012;2:a007641.
    1. Gale E.A. The rise of childhood type 1 diabetes in the 20th century. Diabetes. 2002;51:3353–3361. doi: 10.2337/diabetes.51.12.3353.
    1. The 64 K question in diabetes. Lancet. 1990;336:597–598. doi: 10.1016/0140-6736(90)93395-6.
    1. Baekkeskov S., Nielsen J.H., Marner B., Bilde T., Ludvigsson J., Lernmark Å. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature. 1982;298:167–169. doi: 10.1038/298167a0.
    1. Jones D.B., Hunter N.R., Du G.W. Heat-shock protein 65 as a beta cell antigen of insulin-dependent diabetes. Lancet. 1990;336:583. doi: 10.1016/0140-6736(90)93390-B.
    1. Naser S.A., Thanigachalam S., Dow C.T., Collins M.T. Exploring the role of Mycobacterium avium subspecies paratuberculosis in the pathogenesis of type 1 diabetes mellitus: A pilot study. Gut Pathog. 2013;5:14. doi: 10.1186/1757-4749-5-14.
    1. Scheinin T., Minh N.-N.T., Tuomi T., Miettinen A., Kontiainen S. Islet cell and glutamic acid decarboxylase antibodies and heat-shock protein 65 responses in children with newly diagnosed insulin-dependent diabetes mellitus. Immunol. Lett. 1996;49:123–126. doi: 10.1016/0165-2478(95)02493-X.
    1. Sechi L.A., Rosu V., Pacifico A., Fadda G., Ahmed N., Zanetti S. Humoral immune responses of type 1 diabetes patients to Mycobacterium avium subsp. paratuberculosis lend support to the infectious trigger hypothesis. Clin. Vaccine Immunol. 2008;15:320–326. doi: 10.1128/CVI.00381-07.
    1. Sechi L.A., Paccagnini D., Salza S., Pacifico A., Ahmed N., Zanetti S. Mycobacterium avium subspecies paratuberculosis bacteremia in type 1 diabetes mellitus: An infectious trigger? Clin. Infect. Dis. 2008;46:148–149. doi: 10.1086/524084.
    1. Cossu A., Rosu V., Paccagnini D., Cossu D., Pacifico A., Sechi L.A. MAP3738c and MptD are specific tags of Mycobacterium avium subsp. paratuberculosis infection in type I diabetes mellitus. Clin. Immunol. 2011;141:49–57. doi: 10.1016/j.clim.2011.05.002.
    1. Songini M., Mannu C., Targhetta C., Bruno G. Type 1 diabetes in Sardinia: Facts and hypotheses in the context of worldwide epidemiological data. Acta Diabetol. 2017;54:9–17. doi: 10.1007/s00592-016-0909-2.
    1. Rosu V., Ahmed N., Paccagnini D., Pacifico A., Zanetti S., Sechi L.A. Mycobacterium avium subspecies paratuberculosis is not associated with Type-2 Diabetes Mellitus. Ann. Clin. Microbiol. Antimicrob. 2008;7:9. doi: 10.1186/1476-0711-7-9.
    1. Rosu V., Ahmed N., Paccagnini D., Gerlach G., Fadda G., Hasnain S.E., Zanetti S., Sechi L.A. Specific Immunoassays Confirm Association of Mycobacterium avium Subsp. paratuberculosis with Type-1 but Not Type-2 Diabetes Mellitus. PLoS ONE. 2009;4:e4386. doi: 10.1371/journal.pone.0004386.
    1. Bitti M.L.M., Masala S., Capasso F., Rapini N., Piccinini S., Angelini F., Pierantozzi A., Lidano R., Pietrosanti S., Paccagnini D., et al. Mycobacterium avium subsp. paratuberculosis in an Italian Cohort of Type 1 Diabetes Pediatric Patients. Clin. Dev. Immunol. 2012;2012:1–5. doi: 10.1155/2012/785262.
    1. Cossu A., Ferrannini E., Fallahi P., Antonelli A., Sechi L.A. Antibodies recognizing specific Mycobacterium avium subsp. paratuberculosis’s MAP3738c protein in type 1 diabetes mellitus children are associated with serum Th1 (CXCL10) chemokine. Cytokine. 2013;61:337–339. doi: 10.1016/j.cyto.2012.11.008.
    1. Masala S., Paccagnini D., Cossu D., Brezar V., Pacifico A., Ahmed N., Mallone R., Sechi L.A. Antibodies Recognizing Mycobacterium avium paratuberculosis Epitopes Cross-React with the Beta-Cell Antigen ZnT8 in Sardinian Type 1 Diabetic Patients. PLoS ONE. 2011;6:e26931. doi: 10.1371/journal.pone.0026931.
    1. Scotto M., Afonso G., Larger E., Raverdy C., Lemonnier F.A., Carel J.C., Dubois-Laforgue D., Baz B., Levy D., Gautier J.F., et al. Zinc transporter (ZnT)8(186–194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients. Diabetologia. 2012;55:2026–2031. doi: 10.1007/s00125-012-2543-z.
    1. Niegowska M., Paccagnini D., Mannu C., Targhetta C., Songini M., Sechi L.A. Recognition of ZnT8, Proinsulin, and Homologous MAP Peptides in Sardinian Children at Risk of T1D Precedes Detection of Classical Islet Antibodies. J. Diabetes Res. 2016;2016:1–8. doi: 10.1155/2016/5842701.
    1. Masala S., Cossu D., Piccinini S., Rapini N., Massimi A., Porzio O., Pietrosanti S., Lidano R., Bitti M.L.M., Sechi L.A. Recognition of zinc transporter 8 and MAP3865c homologous epitopes by new-onset type 1 diabetes children from continental Italy. Acta Diabetol. 2014;51:577–585. doi: 10.1007/s00592-014-0558-2.
    1. Masala S., Cossu D., Piccinini S., Rapini N., Mameli G., Bitti M.L.M., Sechi L.A. Proinsulin and MAP3865c homologous epitopes are a target of antibody response in new-onset type 1 diabetes children from continental Italy. Pediatr. Diabetes. 2015;16:189–195. doi: 10.1111/pedi.12269.
    1. Ku htreiber W.M., Tran L., Kim T., Dybala M., Nguyen B., Plager S., Huang D., Janes S., DeFusco A., Baum D., et al. Long-term reduction in hyperglycemia in advanced type 1 diabetes: The value of induced aerobic glycolysis with BCG vaccinations. NPJ Vaccines. 2018;3:23. doi: 10.1038/s41541-018-0062-8.
    1. Kühtreiber W.M., Faustman D.L. BCG Therapy for Type 1 Diabetes: Restoration of Balanced Immunity and Metabolism. Trends Endocrinol. Metab. 2019;30:80–92. doi: 10.1016/j.tem.2018.11.006.
    1. Dow C.T. BCG, Autoimmune Diabetes and M. paratuberculosis. J. Diabetes Metab. Disord. 2018;5:24.
    1. Olsson T., Barcellos L.F., Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat. Rev. Neurol. 2017;13:25–36. doi: 10.1038/nrneurol.2016.187.
    1. Cossu D., Masala S., Sechi L.A. A Sardinian map for multiple sclerosis. Future Microbiol. 2013;8:223–232. doi: 10.2217/fmb.12.135.
    1. Cossu D., Yokoyama K., Hattori N. Bacteria-Host Interactions in Multiple Sclerosis. Front. Microbiol. 2018;9:2966. doi: 10.3389/fmicb.2018.02966.
    1. Cossu D., Cocco E., Paccagnini D., Masala S., Ahmed N., Frau J., Marrosu M.G., Sechi L.A. Association of Mycobacterium avium subsp. paratuberculosis with multiple sclerosis in Sardinian patients. PLoS ONE. 2011;6:e18482. doi: 10.1371/journal.pone.0018482.
    1. Otsubo S., Cossu D., Eda S., Otsubo Y., Sechi L.A., Suzuki T., Iwao Y., Yamamoto S., Kuribayashi T., Momotani E. Seroprevalence of IgG1 and IgG4 class antibodies against Mycobacterium avium subsp. paratuberculosis in Japanese population. Foodborne Pathog. Dis. 2015;12:851–856. doi: 10.1089/fpd.2015.1956.
    1. Frau J., Cossu D., Coghe G., Lorefice L., Fenu G., Melis M., Paccagnini D., Sardu C., Murru M.R., Tranquili S., et al. Mycobacterium avium subsp. paratuberculosis and multiple sclerosis in Sardinian patients: Epidemiology and clinical features. Mult Scler. 2013;19:1437–1442. doi: 10.1177/1352458513477926.
    1. Yokoyama K., Cossu D., Hoshino Y., Tomizawa Y., Momotani E., Hattori N. Anti-Mycobacterial Antibodies in Paired Cerebrospinal Fluid and Serum Samples from Japanese Patients with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder. J. Clin. Med. 2018;7:522. doi: 10.3390/jcm7120522.
    1. Cossu D., Yokoyama K., Hattori N. Conflicting Role of Mycobacterium Species in Multiple Sclerosis. Front. Neurol. 2017;8:216. doi: 10.3389/fneur.2017.00216.
    1. Tea F., Lopez J., Ramanathan S., Merheb V., Lee F., Zou L.A., Pilli D., Patrick E., van der Walt A., Monif M., et al. Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination. Acta Neuropathol. Commun. 2019;7:145. doi: 10.1186/s40478-019-0786-3.
    1. Ristori G., Buzzi M.G., Sabatini U., Giugni E., Bastianello S., Viselli F., Buttinelli C., Ruggieri S., Colonnese C., Pozzilli C., et al. Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis. Neurology. 1999;53:1588–1589. doi: 10.1212/WNL.53.7.1588.
    1. Hughes R.A.C., Berry C.L., Siefert M., Lessof M.H. Relapsing polychondritis. Three cases with a clinicopathological study and literature review. Q. J. Med. 1972;41:363–380.
    1. MacAdam K.P., O’Hanlan M.A., Bluestone R., Pearson C.M. Relapsing polychondritis. Prospective study of 23 patients and a review of the literature. Medicine. 1976;55:193–215. doi: 10.1097/00005792-197605000-00001.
    1. Mathian A., Miyara M., Cohen-Aubart F., Haroche J., Hie M., Pha M., Grenier P., Amoura Z. Relapsing polychondritis: A 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best Pract Res. Clin. Rheumatol. 2016;30:316–333. doi: 10.1016/j.berh.2016.08.001.
    1. Longo L., Greco A., Rea A., Lo Vasco V.R., De Virgilio A., De Vincentiis M. Relapsing polychondritis: A clinical update. Autoimmun. Rev. 2016;15:539–543. doi: 10.1016/j.autrev.2016.02.013.
    1. Sharma A., Gnanapandithan K., Sharma K., Sharma S. Relapsing polychondritis: A review. Clin. Rheumatol. 2013;32:1575–1583. doi: 10.1007/s10067-013-2328-x.
    1. Letko E., Zafirakis P., Baltatzis S., Voudouri A., Livir-Rallatos C., Foster C.S. Relapsing polychondritis: A clinical review. Semin. Arthritis Rheum. 2002;31:384–395. doi: 10.1053/sarh.2002.32586.
    1. Trentham D.E., Le C.H. Relapsing polychondritis. Ann. Intern. Med. 1998;129:114–122. doi: 10.7326/0003-4819-129-2-199807150-00011.
    1. Zeuner M., Straub R.H., Rauh G., Albert E.D., Schölmerich J., Lang B. Relapsing polychondritis: Clinical and immunogenetic analysis of 62 patients. J. Rheumatol. 1997;24:96–101.
    1. Lang B., Rothenfusser A., Lanchbury J.S., Rauh G., Breedveld F., Urlacher A., Albert E., Peter H., Melchers I. Susceptibility to relapsing polychondritis is associated with HLA-DR4. Arthritis Rheum. 1993;36:660–664. doi: 10.1002/art.1780360513.
    1. Hu X., Deutsch A.J., Lenz T.L., Onengut-Gumuscu S., Han B., Chen W.M., Howson J., Todd J., deBakker P., Rich S., et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 2015;47:898–905. doi: 10.1038/ng.3353.
    1. Phoompoung P., Ankasekwinai N., Pithukpakorn M., Foongladda S., Umrod P., Suktitipat B., Mahasirimongkol S., Kiertiburanakul S., Suputtamongkol Y. Factors associated with acquired Anti IFN- γ autoantibody in patients with nontuberculous mycobacterial infection. PLoS ONE. 2017;12:e0176342. doi: 10.1371/journal.pone.0176342.
    1. Menge T., Rzepka R., Melchers I. Monoclonal autoantibodies from patients with autoimmune diseases: Specificity, affinity and crossreactivity of MAbs binding to cytoskeletal and nucleolar epitopes, cartilage antigens and mycobacterial heat-shock protein 60. Immunobiology. 2002;205:1–16. doi: 10.1078/0171-2985-00107.
    1. Murphy S.L., Xu J., Kochanek K.D., Curtin S.C., Arias E. Deaths: Final data for 2015. Natl. Vital Stat Rep. 2017;66:1–75.
    1. Hebert L.E., Weuve J., Scherr P.A., Evans D.A. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013;80:1778–1783. doi: 10.1212/WNL.0b013e31828726f5.
    1. Sherzai D., Sherzai A. Preventing Alzheimer’s: Our Most Urgent Health Care Priority. Am. J. Lifestyle Med. 2019;13:451–461. doi: 10.1177/1559827619843465.
    1. Zuo Z., Qi F., Yang J., Wang X., Wu Y., Wen Y., Yuan Q., Zou J., Guo K., Yao Z.B. Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain. Neurobiol. Dis. 2017;101:27–39. doi: 10.1016/j.nbd.2017.02.001.
    1. Kulkarni S., Mukherjee S., Pandey A., Dahake R., Padmanabhan U., Chowdhary A.S. Bacillus Calmette-Guérin Confers Neuroprotection in a Murine Model of Japanese Encephalitis. Neuroimmunomodulation. 2016;23:278–286. doi: 10.1159/000452171.
    1. Kinney J.W., Bemiller S.M., Murtishaw A.S., Leisgang A.M., Salazar A., Lamb B. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. 2018;4:575–590. doi: 10.1016/j.trci.2018.06.014.
    1. Gofrit O.N., Bercovier H., Klein B.Y., Cohen I.R., Ben-Hur T., Greenblatt C.L. Can immunization with Bacillus Calmette-Guérin (BCG) protect against Alzheimer’s disease? Med. Hypotheses. 2019;123:95–97. doi: 10.1016/j.mehy.2019.01.007.
    1. Gofrit O.N., Klein B.Y., Cohen I.R., Ben-Hur T., Greenblatt C.L., Bercovier H. Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer’s disease in bladder cancer patients. PLoS ONE. 2019;14:e0224433. doi: 10.1371/journal.pone.0224433.
    1. Nikolich-Žugich J. The twilight of immunity: Emerging concepts in aging of the immune system. Nat. Immunol. 2018;19:10–19. doi: 10.1038/s41590-017-0006-x.
    1. Panza F., Lozupone M., Solfrizzi V., Watling M., Imbimbo B.P. Time to test antibacterial therapy in Alzheimer’s disease. Brain. 2019;142:2905–2929. doi: 10.1093/brain/awz244.
    1. Bu X.L., Yao X.Q., Jiao S.S., Zeng F., Liu Y.H., Xiang Y., Liang C., Wang Q., Wang X., Cao H. A study on the association between infectious burden and Alzheimer’s disease. Eur. J. Neurol. 2015;22:1519–1525. doi: 10.1111/ene.12477.
    1. Dow C.T. CMV Driven Immunosenescence and Alzheimer’s Disease. J. Neuroinfect. Dis. 2015;6:195. doi: 10.4172/2314-7326.1000195.
    1. Dominy S.S., Lynch C., Ermini F., Benedyk M., Marczyk A., Konradi A., Nguyen M., Haditsch U., Raha D., Griffin C., et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv. 2019;5:eaau3333. doi: 10.1126/sciadv.aau3333.
    1. Broxmeyer L. Are the Infectious Roots of Alzheimer’s Buried Deep in the Past? J. Mol. Path Epidemol. 2017;2:S2.
    1. Broxmeyer L. Thinking the unthinkable: Alzheimer’s, Creutzfeldt-Jakob and Mad Cow disease: The age-related reemergence of virulent, foodborne, bovine tuberculosis or losing your mind for the sake of a shake or burger. Med. Hypotheses. 2005;64:699–705. doi: 10.1016/j.mehy.2004.10.008.
    1. Umeda T., Ono K., Sakai A., Yamashita M., Mizuguchi M., Klein W.L., Yamada M., Mori H., Tomiyama T. Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers. Brain. 2016;139:1568–1586. doi: 10.1093/brain/aww042.
    1. Iizuka T., Morimoto K., Sasaki Y., Kameyama M., Kurashima A., Hayasaka K., Ogata H., Goto H. Preventive Effect of Rifampicin on Alzheimer Disease Needs at Least 450 mg Daily for 1 Year: An FDG-PET Follow-Up Study. Dement. Geriatr. Cogn. Dis. Extra. 2017;7:204–214. doi: 10.1159/000477343.
    1. Netea M.G., van Crevel R. BCG-induced protection: Effects on innate immune memory. Semin Immunol. 2014;26:512–517. doi: 10.1016/j.smim.2014.09.006.
    1. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. doi: 10.1126/science.123.3191.309.
    1. Vander M.G., Heiden L.C., Cantley C.B. Thompson, Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009;324:e1029–e1033. doi: 10.1126/science.1160809.
    1. Lerner T.R., Borel S., Gutierrez M.G. The innate immune response in human tuberculosis. Cell Microbiol. 2015;17:1277–1285. doi: 10.1111/cmi.12480.
    1. O’Garra A., Redford P.S., McNab F.W., Bloom C.I., Wilkinson R.J., Berry P. The immune response in tuberculosis. Annu. Rev. Immunol. 2013;31:475–527. doi: 10.1146/annurev-immunol-032712-095939.
    1. Chen Z., Liu M., Li L., Chen L. Involvement of the Warburg effect in non-tumor diseases processes. J. Cell Physiol. 2018;233:2839–2849. doi: 10.1002/jcp.25998.
    1. Tannahill G.M., Iraci N., Gaude E., Frezza C., Pluchino S. Metabolic reprograming of mononuclear phagocytes in progressive multiple sclerosis. Front. Immunol. 2015;6:106. doi: 10.3389/fimmu.2015.00106.
    1. Atlante A., de Bari L., Bobba A., Amadoro G. A disease with a sweet tooth: Exploring the Warburg effect in Alzheimer’s disease. Biogerontology. 2017;18:301–319. doi: 10.1007/s10522-017-9692-x.
    1. Massari F., Ciccarese C., Santoni M., Iacovelli R., Mazzucchelli R., Piva F., Scarpelli M., Berardi R., Tortora G., Lopez-Beltran A., et al. Metabolic phenotype of bladder cancer. Cancer Treat. Rev. 2016;45:46–57. doi: 10.1016/j.ctrv.2016.03.005.
    1. Shi L., Eugenin E.A., Subbian S. Immunometabolism in Tuberculosis. Front. Immunol. 2016;7:150. doi: 10.3389/fimmu.2016.00150.

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